Therapies for Cancer
(San Francisco, CA, April 26, 2012) – Researchers at California Pacific Medical Center Research Institute (CPMCRI), part of the Sutter Health network, have found that increased expression of a gene in the deadly skin cancer melanoma can increase the risk of death from the tumor, and represents a possible new target for treatment of melanomas that express high levels of this gene. The findings will be published in Proceedings of the National Academy of Sciences (PNAS).
It is the first time the role of PHIP, pleckstrin homology domain-interacting protein, has been reported in any cancer, according to the study. The findings could lead to new therapies for treating melanoma and other types of cancer where PHIP is active. The study, “Pleckstrin Homology Domain-Interacting Protein (PHIP) as a Marker and Mediator of Melanoma Metastasis,”
“We’ve shown that this gene is a marker of increased risk of spread and of death due to melanoma,’’
Researchers examined the effects of high levels of the PHIP protein on the spread or metastasis of melanoma both in mice and in human tissues from melanoma patients, and showed that tumors with higher expression of PHIP were associated with reduced survival in both of these studies. For example, researchers suppressed PHIP in melanomas in mice, and they found that mice in this category lived longer than the mice that had melanomas with active PHIP.
In addition, the researchers studied tissues from a cohort of 345 patients with melanoma. They found that nearly one-third of them had the highest levels of PHIP, which correlated with significantly reduced survival when compared with melanomas with lower levels of PHIP expression.
“We learned in both mice and humans, that the more of this (PHIP) a tumor has, the higher the risk is for the cancer spreading and the lower the survival,” Kashani-Sabet said.
The researchers also considered the genetic makeup of melanoma tumors to understand which melanomas might carry increased amounts of PHIP. Recent studies have centered on the role of other genes in melanoma, particularly, the gene known as BRAF. BRAF is mutated in about 50 percent of melanomas. An inhibitor of mutated BRAF prolonged the survival of patients with metastatic melanoma, and was approved by the U.S. Food and Drug Administration in 2011. However, the genes that are responsible for the metastasis of melanomas without this mutation are unknown, and few effective therapies exist for patients whose melanomas do not have a BRAF mutation.
In this study, high PHIP levels were specifically found in melanomas without a mutation in BRAF. In fact, many melanomas with high levels of PHIP also lacked mutations in two other important genes called NRAS and PTEN. Therefore, PHIP may be responsible for the aggressive behavior of "triple-negative"
The finding is significant because researchers hope that future therapies for patients with melanoma and other cancers can be developed by targeting a gene such as PHIP that promotes spread of the tumor.
Next steps include confirming that PHIP is a marker for melanomas in human tissue specimens from other institutions and other countries, Kashani–Sabet said. He also plans to study other cancers where PHIP may play an important role.
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